Introduction: Low birth weight (LBW) is one of the most serious challenges in maternal and child health in developing countries. Neonatal sepsis is responsible for about 30-50% of the total neonatal deaths in developing countries. Given the high prevalence of Very Low Birth Weight (VLBW) neonates and the increasing incidence of sepsis in this population, there is a need to study the clinical and bacteriological profile of sepsis. Aim: To study the clinico-bacteriological profile of neonatal sepsis in VLBW neonates (Birth weight <1500 gm) in a tertiary care NICU in central India. Materials and Methods: The descriptive observational study was conducted among VLBW neonates with clinically suspected sepsis admitted to the NICU of Indira Gandhi Government Medical College and Mayo Hospital in Nagpur, Maharashtra, India, from November 2019 to October 2021. All 160 VLBW neonates with clinically suspected sepsis and positive sepsis screen consisting of four parameters {Absolute Neutrophil Count (ANC), Total Leucocyte Count (TLC), Immature/Total Neutrophil Ratio (I/T Ratio), C-Reactive Protein (CRP)+} and whose mothers provided informed consent were included in the study within 24 hours of admission. Details such as demographic data, maternal risk factors and type of delivery, clinical signs of sepsis presentation, any Central Nervous System (CNS) signs, day of onset of sepsis, sepsis screen parameters (CRP, TLC, ANC, I/T Ratio), blood culture, and Cerebro-spinal Fluid (CSF) examination findings were studied. Continuous variables were evaluated using the student t-test, and categorical variables were evaluated using the chi-square test. Results: There were 96 (60%) males and 64 (40%) females. In the sepsis screen parameters, the majority of the neonates were CRP positive 148 (92.3%) followed by TLC positive among 119 (74.38%) neonates. Lethargy was the most common clinical presentation among 147 (91.88%) neonates followed by difficulty in feeding among 121 (75.63%) neonates. Blood culture was positive among 61 (38.13%) neonates, and Escherichia coli was the most common organism isolated among 21 (34.43%) neonates. Conclusion: The most common clinical presentation of neonatal sepsis was lethargy followed by difficulty in feeding. In the present study, the most common organism isolated was E.coli.